The overall goals of this ongoing research project are to study the metabolism, excretion and persistence of long-acting narcotics, using methadone as a prototypic compound, in man, primarily in tolerant humans maintained on methadone, and in both naive and tolerant animals, and to study interactions between methadone and other drugs or agents which may alter its disposition and thus its effects. New techniques using gas chromatography and mass spectrometry continue to be developed to carry out these studies. Specific recent objectives have been to develop new techniques using stable isotope technology so that the disposition of the separate active and inactive enantiomers of methadone can be studied simultaneously in otherwise healthy patients in maintenance treatment as well as in well defined patient subgroups. Three different stable-labeled methadone compounds are used in these studies (d3, d5, and d8). Other new techniques using direct probe-chemical ionization-mass spectrometry have been developed for simulataneous determination of unchanged methadone and seven metabolites in human urine. These techniques have been applied to studies of urinary excretion of methadone in otherwise healthy maintenace patients and patients with chronic liver disease; significant differences have been observed. Studies of the effects of route of administration on plasma levels and disappearance rates of methadone in the rat have been carried out. Studies of drug interactions between methadone and both ethanol and estrogen in the rat and between methadone and both ethanol and phenytoin in humans have been performed. Other studies of potential drug interactions are in progress.